Sarcopenic Obesity: An Emerging Public Health Problem

Population aging and the obesity epidemic are important global public health problems that pose an unprecedented threat to the physical and mental health of the elderly and health systems worldwide. Sarcopenic obesity (SO) is a new category of obesity and a high-risk geriatric syndrome in the elderly. SO is associated with many adverse health consequences such as frailty, falls, disability, and increased morbidity and mortality. The core mechanism of SO is the vicious circle between myocytes and adipocytes. In order to implement effective prevention and treatment strategies and reduce adverse clinical outcomes, it is essential to further our understanding of SO in the elderly. Herein, we reviewed the definition, diagnosis, epidemiology, pathogenesis, and treatment of SO in older adults.

. The potential etiology and pathogenesis of sarcopenic obesity (SO). In the process of aging, an unhealthy diet, sedentary habits, changes in body composition, hormone changes and a variety of chronic diseases in elderly cause chronic lowgrade inflammation, oxidative stress, and insulin resistance, resulting in SO. The core mechanism of SO is the vicious circle between myocytes and adipocytes. SKM, skeletal muscle; MPS, skeletal muscle protein synthesis; MPB, muscle protein breakdown; GLUT4, glucose transporter type 4; IGF-1, insulin-like growth factor 1; IL, interleukin; MCP-1, monocyte chemoattractant protein 1.

Definition and measurement
Baumgartner first proposed the concept of "Sarcopenic Obesity" in 2000 and defined it as a phenotype of copresence of sarcopenia and obesity [18]. This definition was supported by a more recent critical appraisal of the definition and diagnostic criteria of SO based on a systematic review which noted that most existing studies defined SO based on the co-existence of obesity and sarcopenia [19] (Table 1). SO is a complex geriatric syndrome characterized by an aged-associated reduced muscle mass and dysfunction and excess adiposity [11,20]. Therefore, individuals with SO have a double burden of malnutrition and are at an increased risk of frailty, disability, morbidity, and mortality. Due to the lack of consensus on the definition and diagnostic criteria for SO, accurate diagnostic assessment of SO is extremely challenging. Further, previous studies were characterized by significant differences in the measurement methods used to define sarcopenia and obesity ( Table 2). A systematic review reported that there are 19 methods to evaluate sarcopenia and 10 methods to evaluate obesity. The most used methods to define sarcopenia and obesity are appendicular skeletal muscle (ASM) divided by weight (ASM/wt) or adjusted by height in meters squared (ASM/h 2 ) and body mass index (BMI) or percentage of body fat (PBF), respectively [19]. Rough indicators such as weight and BMI are not recommended for the assessment of body composition in the elderly as these cannot distinguish between fat and muscle mass. Dual-energy X-ray absorptiometry (DXA) is a reliable technique for body composition analysis owing to its safety, repeatability, and accuracy; however, it is associated with a risk of radiation exposure [31]. Bioimpedance analysis (BIA) is a quick and portable technique for measuring body composition [32], which is suitable for large-scale epidemiological investigations and can replace DXA. Although computed tomography and magnetic resonance imaging are more accurate body composition analysis methods, they have limited clinical applications because of their high cost, radiation exposure, and need for qualified personnel [33].

Definition of sarcopenia
Sarcopenia was first defined by Rosenberg in 1989 [34]. Sarcopenia refers to a group of age-related syndromes of decreased skeletal muscle content, decreased muscle strength, and muscle dysfunction, which can cause weakness, disability, and falls [35]. The ICD-10 code for sarcopenia was introduced in 2016 (M62.84), facilitating the assessment, diagnosis, and treatment of sarcopenia [36].

Diagnosis of sarcopenia
Sarcopenia is defined by a variety of variables such as skeletal muscle mass (SMM), muscle strength, and physical performance ( Table 2). SMM can be calculated using the following measurements: 1) ASM / ht 2 [24]; 2) ASM/wt [37]; 3) based on residual height correction and total fat muscle mass [38]; 4) ASM adjusted by BMI [26]; 5) unadjusted or absolute appendicular lean muscle [26]; and 6) unadjusted or adjusted body mass, height, or BMI [24]. Studies have shown that SMM is not linearly related to muscle strength. Muscle strength decays faster than SMM and is a more valuable indicator of the overall health of the elderly [39]. Muscle strength can be evaluated by measuring grip strength using a hand dynamometer, or by measuring knee extension strength [40]. The assessment measures of physical performance include gait speed, short physical performance battery, and timed up-and-go [5,19]. Diagnostic criteria for sarcopenia have been proposed by different international working groups. The International Sarcopenia Working Group defined sarcopenia as a decrease in lean tissue and physical function of the whole body or limbs (walking speed ≤ 1/s) [25].
The European Working Group for the study of Sarcopenia (EWGSOP) defined sarcopenia based on the combination of SMM, assessed using DXA or BIA, and muscle function, indicated by muscle strength or performance [24]. In the clinical setting, EWGSOP recommends the assessment of walking speed to evaluate frailty, with a threshold of < 0.8 m/s; patients with sarcopenia and impaired physical performance (gait speed ≤ 0.8 m/s) are considered to have severe sarcopenia. Regarding grip strength, the EWGSOP has proposed different cut-offs based on an individual's BMI. The 2019 updated version of the EWGSOP2 consensus recommends that muscle strength should be measured before SMM, and that sarcopenia should be suspected in patients with reduced muscle strength [29].
The Foundation for the National Institutes of Health (FNIH) Sarcopenia Project proposed to define sarcopenia as low SMM, low muscle strength, and physical decline. The FHIH recommends the use of DXA to measure SMM, with corrections for BMI [26].
The Asian Working Group for Sarcopenia (AWGS) [27] proposed diagnostic criteria for sarcopenia applicable to Asian populations, using grip strength and physical function for preliminary screening. The diagnostic process for sarcopenia proposed by the AWGS includes a detailed protocol that involves self-assessment, preliminary screening, diagnosis, and severity assessment. In the primary care setting and hospital setting, preliminary screening of sarcopenia can be based on a measurement of calf circumference (<34 cm in men, < 33 cm in women), the SARC-F scale (≥4), or SARC-Calf scale (≥11). DXA or BIA can be used to improve SMM measurements during hospitalization. The AWGS defines sarcopenia as a decrease in SMM and muscle strength or physical activity. The patients with reduced SMM and decreased muscle strength and reduced physical activity are considered to have severe sarcopenia [30].

Diagnostic criteria for obesity
In the SO study, obesity was defined as BMI ≥ 30 kg/m 2 [4], increased PBF (men ≥ 27% or 28%, women ≥ 35%, 38%, or 40%, depending on specific study criteria) [5,6], and waist circumference higher than the populationspecific quartile [41] or higher than the World Health Organization (WHO)-recommended waist circumference (male ≥ 102 cm, female ≥ 88 cm) [42]. The American Association of Clinical Endocrinologists (AACE) proposed the use of PBF to define obesity, where PBF > 25% and > 35% represent obesity in males and females, respectively [25]. So far, there are no cut-off points for BMI, PBF, and waist circumference for obesity in the elderly. Adipose tissue can be separated into subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT). Currently, there is a lack of relevant diagnostic guidelines to define obesity based on SAT and VAT. Indeed, some scholars have proposed that future studies should focus on distinguishing between sarcopenic subcutaneous obesity and sarcopenic visceral obesity and use the standardized VAT/SAT ratio to diagnose SO [43].

Prevalence
Due to the heterogeneity of the definition of SO, the reported prevalence of SO is variable and ranges from 2.75% to 20% or more [19]. Further, the prevalence of SO differs according to gender, race, and age because of the different standards adopted by different countries. A systematic review reported that the global prevalence of SO in the elderly was 11% [3]. It also showed that the overall morbidity rate of SO in the elderly aged 75 and older was 23%, indicating that the prevalence of SO increases with age. The potential causes include the changes in hormones and body composition (muscle atrophy and adipose tissue accumulation) caused by aging. There was no sex difference in the prevalence of SO among the elderly, suggesting that both women and men are at a high risk [5,6]. The prevalence of SO was higher in South America and North America, and the pooled prevalence of SO was higher in inpatients than in community residents, indicating that malnutrition and immobility are linked to the development of SO in the elderly in the hospital.

Etiology and Pathogenesis
The etiology and pathogenesis of SO are intertwined and intricate. The core biological factors leading to SO are changes in body composition related to aging, hormonal changes, the interplay between metabolism and inflammation, environmental factors (unhealthy diet and lack of exercise), and chronic diseases [5,6,11,44]. Aging and obesity cause atrophy of fast type II muscle fibers and a switch to slow type I muscle fibers and neurodegeneration, leading to loss of muscle neurotrophic effects and promotion of intramyocellular lipid (IMCL) deposition. A prominent manifestation of SO is anabolic resistance (AR), which is characterized by reduced skeletal muscle protein synthesis rates and increased muscle protein degradation rates [11,45]. The key pathophysiological mechanism of SO is a vicious cycle between myocytes and adipocytes [6]. Obesity is characterized by the expansion of adipose tissue, which leads to adipose tissue inflammation and dysfunction, leading to the over-production of fatty acids. When the number of fatty acids exceeds the oxidation capacity of skeletal muscle, IMCL [46] is formed, and this affects the function of the GLUT4 transporter. This subsequently leads to reduced glucose utilization and increased fatty acid oxidation in mitochondria, which leads to impaired insulin sensitivity of skeletal muscle, inhibition of mitochondrial respiration, reactive oxygen species formation, muscle cytotoxicity, catabolism, and inflammation. Muscle intercellular adipose tissue and IMCL are characterized by dysregulation of adipokines and cytokines (↑TNF-α, ↑IL-6, ↑leptin, ↑IL-1β, ↑MCP-1, ↓adiponectin), which induce IR and lipotoxicity, and eventually lead to sarcopenia [47][48][49][50]. At the same time, adipose tissue enhances the secretion of pro-inflammatory actin in muscle tissue. On the other hand, myocytokines (↓IL-15, ↓irisin, ↓IGF-1, ↑myostatin, impaired IL-6 secretion) may lead to muscle atrophy and dysfunction, they may play an endocrine role to aggravate fatty tissue inflammation and propagate a pro-inflammatory state between myocytes and adipocytes [5,[49][50][51][52]. A summary of the possible mechanisms is shown in Figure 1.

Age-related changes in body composition
Under the influence of lifestyle factors and hormone levels, body composition changes significantly with age. The main changes are an increase in total fat mass, which peaks between 60 and 75 years old, and a decrease in peripheral subcutaneous fat, preferential accumulation of visceral fat, and ectopic fat infiltration in various organs. By comparison, SMM and muscle strength start to decrease from approximately 30 years of age, and the rate of decline of muscle mass accelerates significantly in adults over 60 years old [53]. Therefore, the body weight of older people is mainly composed of adipose tissue rather than lean tissue [5,6].

Hormonal changes
Hormonal changes related to aging include insulin resistance, decreased thyroid hormone level, and increased levels of cortisol, growth hormones, insulin-like growth factor (IGF-1), sex hormones, and dehydroisoandrosterone sulfate, which all contribute to SO. In postmenopausal women, body composition changes result in increased adipose tissue, visceral fat infiltration, and decreased SMM [5]. In men, the decline in testosterone levels with aging has an adverse effect on the distribution of muscle and adipose tissue [5].

Inflammation and metabolism
SO is considered to represent a sub-acute, chronic proinflammatory state, which hinders metabolic processes (oxidative stress and insulin resistance), destroys the function of adipose and muscle, and increases the risk of chronic disease [11,53]. Recent studies have shown that there is a key crosstalk between metabolism and inflammation, which has led to increased focus on the concept of metabolic inflammation [11]. In SO, adipocytes accumulate in muscle tissue and other organs (heart, liver and pancreas and so on) and secrete proinflammatory cytokines (TNF-α, IL-6, IL-1 and leptin), thus leading to the infiltration of inflammatory cells and inducing insulin resistance and lipotoxicity, which directly affects skeletal muscle and accelerates muscle protein degradation and apoptosis, and promotes muscle tissue reduction and adipose tissue accumulation through inflammation and oxidative stress [5,6,54,55]. The levels of IL-6 and TNF are increased by leptin, thereby reducing the anabolism of IGF-1 [56]. The decrease in IGF-1 and age-related testosterone levels increases the incidence of frailty [57]. Adiponectin is inversely correlated with age and obesity and counteracts the effect of leptin. The increase in TNF can directly inhibit the effect of adiponectin and inhibit the synthesis of muscle proteins and mitochondrial function. Obesity can also cause leptin resistance, resulting in reduced breakdown of lipid oxidative products and ectopic fat deposition [57].

Myocyte mechanism
Numerous molecules (TNF-α, IL-6, IL-1, adiponectin, leptin, muscle somatostatin, sex hormones (testosterone and estrogen), growth hormone, insulin and glucocorticoid, and irisin) have been implicated in the pathogenesis of SO [50]. Aging stimulates fat to infiltrate muscles, and obesity promotes fatty infiltration of other organs such as the liver, pancreas, and heart. Lipid deposition in muscle cells promotes lipotoxicity and inflammation and induces the de-differentiation of mesenchymal progenitor cells expressing adipose tissue genes. Impaired muscle regeneration capacity may lead to fibrosis of muscle tissue, impaired mitochondrial function, increased production of reactive oxygen species, upregulation of myostatin expression, impaired fatty acid oxidation, and reduced lipolysis, thereby promoting insulin resistance and impairing muscle function [5].

Influence of environmental and chronic diseases
The onset of SO is influenced by several lifestyle factors, of which the most important are dietary changes and lack of physical activity. Aging itself leads to obesity and reduced physical activity. Further, the dietary pattern of elderly people, which is often characterized by insufficient protein intake combined with excess dietary calorie intake that is rich in saturated fatty acids, coupled with a sedentary lifestyle promotes the occurrence of sarcopenic obesity [11]. SO shares a common pathogenic mechanism with a variety of chronic diseases such as diabetes, cardiovascular disease, and cancer, among others [7,8,49]. SO can lead to a variety of pathophysiological changes, such as excessive secretion of pro-inflammatory cytokines by adipose tissue, changes in the expression of adipocytokines by adipocytes, and fat accumulation in muscle [6,12]. Skeletal muscle cell atrophy reduces the expression of GLUT4 in muscle tissue and decreases the demand for insulin-dependent glucose uptake [58]. The pro-inflammatory state and lipid accumulation in muscle fibers induce phosphorylation and deactivate insulin receptors and their substrates [19], resulting in insulin resistance and AR. Insulin resistance is the core mechanism of SO associated with cardiovascular metabolic diseases and cancer [49,50].

Preventive and therapeutic strategies
At present, the optimal treatment of SO has not been established. Nutritional interventions, such as a hypocaloric diet, and exercise training or physical therapy are the mainstay of SO prevention and treatment to achieve changes in body composition (muscle gain and fat reduction) and improve the functional status and quality of life of elderly patients. However, solely focusing on weight loss per se is not desirable for the elderly because weight loss may actually pose health risks such as loss of muscle and bone mass.

Diet intervention strategies
The nutritional strategies for the prevention of SO in the elderly include hypocaloric diets and high protein and micronutrients supplementation [5,6]. Extremely lowcalorie diets and rapid calorie restriction for the management of sarcopenic obese older adults are strongly discouraged, because they can have harmful effects on SMM, bone mineral density, and the micronutrient status, and increase the risk of hypovolemia and electrolyte disorders. [5,6]. Instead, the optimal and safe range of calorie restriction is about 200-750 kcal per day [59]. It is recommended that elderly people should consume larger amounts of high-quality protein (aiming for 1-1.2 g/kg/d) [5], with an even higher intake (1.2-1.5 g/kg/d) [60] recommended for elderly patients with sarcopenia or other chronic diseases; however, patients with renal insufficiency should monitor their protein intake. Intake of dietary essential amino acids (EAAs), and especially high leucine content, promotes muscle protein synthesis [5]. Ensuring sufficient intake of trace elements could improve several sarcopenic parameters and physical frailty, with most guidelines recommending supplementation with 1200 mg of calcium and vitamin D (800 to 1000 IU daily) [61]. The American Academy of Geriatrics recommends a daily intake of vitamin D3 (1,000 IU) and calcium in the elderly non-hospitalized population older than 65 years to maintain serum vitamin D levels ≥ 30 ng/ml [62]. A recent review proposed a new approach to dietary recommendations based on the gut microbiota profile in patients with SO based on the finding that a high-protein diet with an elevated concentration of EAA and increased dietary fiber intake may promote the eugenics of the intestinal microbiota [63].

Exercise interventions
Physical activity (aerobic exercise, resistance exercise, and combination training) is a powerful treatment strategy to counteract one or more of the biological effects of SO and has been demonstrated to promote insulin sensitivity [7,64], reduce oxidative stress [65], induce mitochondrial biosynthesis, ameliorate inflammation, and eliminate muscle cell apoptosis, among other positive effects [5,58,[63][64][65][66].
Aerobic exercise can ameliorate cardiopulmonary function and reduce mortality [5,67], and resistance training is effective in enhancing muscle function and strength in the elderly [68]. Because the elderly often suffer from various chronic diseases, a tailored exercise program that considers these comorbidities and associated physical limitations is recommended by most guidelines. Aerobic exercise should aim for a peak heart rate of 65% with a target heart rate zone of 70%-85% of the peak. On the other hand, resistance training should focus on 1-2 muscle groups and include 8-12 repetitions, with an initial intensity of 65% of 1 repetition maximum (1RM), aiming to reach 2-3 repetitions with an intensity of 75% 1RM. Resistance training should aim to achieve fatigue rather than exhaustion to prevent musculoskeletal injury [60,69].

Emerging treatments for SO
Although many emerging pharmacological interventions have been studied, such as testosterone supplementation [13], selective androgen receptor modulators [14], myostatin inhibitors [15], and anti-obesity drugs [5,6], there are no approved drugs for the treatment of SO in the elderly. A recent systematic review of treatment strategies for SO showed that electrical acupuncture and whole-body electromyostimulation associated with nutritional supplementation are new and effective strategies to induce changes in body composition [16].
Whole body vibration therapy has become a safe and convenient technique to cause neuromuscular activation and simulate the contraction of skeletal muscle [70]. A randomized controlled clinical trial of 90 elderly men found that whole-body vibration therapy significantly increased muscle strength and physical function in older people [71]. This therapy has the potential to replace traditional exercise for the treatment of SO among elderly people as it is better tolerated and can reduce fat mass (FM) and increase muscle strength. Nevertheless, this therapy is still in the research stage and there is a need for further clinical studies to verify its efficacy in routine clinical practice.
A recent study demonstrated that the adenosine A2B receptor (A2B) is highly expressed in muscle tissue and brown adipose tissue (BAT) and may be a target for SO [17]. Adenosine / A2B signaling pathway display the core function in maintaining the quality and function of skeletal muscle. Stimulation of A2B could play a key role in anti-aging and anti-obesity effects and restore skeletal muscle function and quality to adolescent levels. At the same time, A2B activation also reduced the impaired BAT function and induced white adipose tissue browning associated with age and obesity. However, the current evidence regarding the role of adenosine/A2B signaling is limited to animal studies, and more research is needed to verify the role of this signaling pathway in humans.

Conclusions and perspectives
The prevalence of SO increases with age and it is estimated that more than one-tenth of the elderly population suffer from SO globally. This has important public health consequences as SO is associated with frailty, falls, disability, and increased morbidity and mortality, and places a heavy burden on individuals, society, and the medical system. To further our understanding of SO, it is essential that clinicians and researchers establish a universal consensus for the definition and diagnosis of SO and focus on SO screening to identify susceptible individuals early. Additional studies are warranted to clarify the pathogenesis of SO and formulate the best diet and exercise intervention scheme to provide tailored treatments and promote healthy aging. In conclusion, establishing an accurate definition and diagnostic criteria for SO, and introducing effective preventative and treatment options have become an urgent task for researchers and clinicians.